Population-based pharmacogenomic assessment of QT prolongation

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Abstract Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such as prolongation of the QT interval, is a relevant clinical topic because it has regulatory consequences (labelling and withdrawal of drugs) and is associated with potentially fatal patient-level outcomes (ventricular arrhythmias and Torsade de Pointes). We propose here to leverage the extensive phenotypic and genotypic data resources of the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH), and the ability to link these data to other health plan databases, namely our pharmacy, electrocardiogram (ECG) and outpatient/inpatient utilization databases. In particular, we will use the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort members (n=110,266; n=69,276 with 1 or more available ECGs; 52,667 with two or more ECGs). Our ability to conduct longitudinal analyses of the QT interval over up to 20 years in a large and ethnically diverse population (The GERA cohort is 78% Caucasian, 6% Asian/Pacific Islander, 6% Latino, 3% African-American, 5% other or mixed) and to identify and characterize genetic loci that influence adverse drug reactions is unique and will advance our understanding of the genetic basis of cardiac toxicity of commonly prescribed medications. Replication of findings in Europeans will be sought in 70,944 Caucasian subjects with ECG, genome-wide and medication data in the UK Biobank. We will perform functional annotation of replicated hits to shed light on biological pathways and tissues involved. In addition, to complement this approach and to more fully address the downstream clinical significance of QT prolongation, we will also examine: a) genetic predictors of incident ventricular arrhythmias and of Torsade de Pointes; b) whether the identified gene by drug interactions are associated with these adverse outcomes and c) degree of mediation by QTc prolongation. Our results will be shared with the Pharmacogenomics Research Network (PGRN) for replication and meta-analytical purposes. Our long-term goal is to advance the field of the genetic basis of drug cardiotoxicity and its downstream consequences that will inform therapeutic considerations.